Ultraviolet (UV) light constitutes a major environmental insult to all exposed tissues of the body, including those comprising the cornea and other underlying ocular structures. UV light can damage a wide variety of macromolecular components ranging from DNA, to proteins, to lipids, with damage to DNA resulting, for example, in cancer. This damage can be direct, or it can be indirect through the generation of active oxygen species (AOS). Corneal epithelial (CE) cells, however, seems to be refractory to such damage. Cancers of these cells are extra-ordinarily rare, even though this tissue is transparent and constantly exposed to mutagenic UV light and other sources of AOS such as H2O2. Our results suggest that one mechanism that CE cells have evolved to prevent damage to their DNA involves ferritin in a nuclear localization, rather than the cytoplasmic location it has in all other cell types. This molecule seems to directly diminish the effects of UV-produced AOS to DNA and possibly other nuclear components-most likely be sequestering free iron which acts as a catalyst in generating hydroxyl radicals, the most damaging AOS. The areas that will be investigated further: 1) the mechanisms involved in the nuclear localization of ferritin in CE cells, 2) how this molecule protects DNA from UV-induced and other oxidative damage, and 3) how production of the molecule is developmentally regulated. For the nuclear localization in CE cells two possible mechanisms will be examined. One is the involvement of a CE tissue-specific chaperone that is capable of carrying ferritin """"""""piggy-back"""""""" into the nucleus, and the other is that some specialization of the CE cell nucleus itself is responsible for the transport. Then the role of iron sequestration in decreasing UV-induced damage to the DNA of CE cells will be evaluated further. It will also be determined whether this protection extends to other sources of AOS, and whether similar protection can be afforded to other cell types in which UV-induced and other sources of AOS potentially have deleterious effects. Lastly, the regulation of production of nuclear ferritin will be investigated-chiefly at the early, pre-ferritin stage of development, which our preliminary data suggest may be under a unique type of translational regulation involving low levels of iron plus another component(s) such as thyroxine. This mechanism may produce a low-iron ferritin that is highly efficient at iron sequestration and therefore protection against damage by AOS.
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